The present invention lies in the field of lipophilic pharmaceutical formulations for oral administration. More specifically, the present invention lies in the field of pharmaceutical formulations including a digestible vegetable oil and a phenolic antioxidant such as probucol.
Probucol is a commercially available drug marketed under the trademark Lorelco.RTM. (Marion Merrell Dow Pharmaceuticals, Inc., Kansas City, Mo.). It is a water-insoluble antioxidant, chemically related to the widely used food additives 2,[3]-tert-butyl-4-hydroxyanisole (BHA) and 2,6-di-tert-butyl-4-methylphenol (BHT). Today, probucol is used primarily to lower serum cholesterol levels in hypercholesterolemic patients. However, recent work has shown that it may also be used to treat viral infections such as AIDS. The anti-viral properties of probucol are discussed in U.S. Pat. No. 4,985,465, which is assigned to Vyrex Corporation (the assignee of the present invention) and incorporated herein by reference for all purposes.
Probucol's chemical name is bis(3,5-di-tert-butyl-4-hydroxyphenyl) acetone mercaptole, and it has the following structure: ##STR1##
Probucol is commonly administered in the form of tablets containing celluloses and other excipients. This form of probucol is poorly absorbed into the blood, and is excreted in a substantially unchanged form. Further, the tablet form of probucol is absorbed at significantly different rates and in different amounts by different patients. In one study (Heeg et al., Plasma levels of probucol in man after single and repeated oral doses. La Nouvelle Presse Medicale, 9(40), 2990-2994 (1980)), peak levels of probucol in sera were found to differ by as much as a factor of about 20 from patient to patient. These results are presented in FIG. 1 which shows how the concentration of probucol in blood changed with time in six patients who received a 250 mg dose. (FIG. 1 is a reconstruction of a semilogarithmic plot presented in the above article).
Because the tablet form of probucol has these various problems, an alternative delivery means having improved absorption characteristics would be highly desirable. An oil-based delivery vehicle might be expected to improve absorption of oral doses, as probucol is substantially water insoluble. However, very little work has been performed in this area. Two publications do describe studies in which probucol was administered to rats via oil-containing formulations, but neither of these publications describes a formulation optimized for high absorption and uniform absorption. In addition, neither of these studies involved a direct comparison of tablet-form and oil-containing delivery vehicles. Thus, it is possible that the formulations described in these references performed no better than the Lorelco.RTM. tablets.
One of these references (J. F. Heeg et al., Pharmacokinetics of probucol in male rats. Journal of Pharmaceutical Sciences, 73 (12), 1758-1763 (1984)), describes the use of an emulsion of water and coconut oil to orally deliver probucol to a series of test rats as part of a pharmacokinetic study. The emulsion was prepared by combining a solution of approximately 1% probucol in coconut oil (a naturally occurring saturated medium chain triglyceride) with an aqueous mixture of glucose, lecithin and detergent. This emulsion was administered to the rats orally through stainless-steel feeding needles. At certain times after administration, selected rats were decapitated and exsanguinated to test the plasma distribution and clearance of probucol. The absorption results were unimpressive, prompting the authors to conclude that the formulation gave poor availability, and that further studies of oil-based delivery vehicles were needed. Further, because only two rats were analyzed at each time point, this study could not show whether the probucol is uniformly absorbed from individual to individual.
In another study (K. J. Palin et al., The effect of oil on the absorption of probucol in the rat. Journal of Pharmacy and Pharmacology, 35 (supplement) 85P (1983)), investigators measured the plasma concentration of probucol in rats orally administered solutions of probucol in peanut oil and in medium chain triglyceride. The concentration of probucol used in the test solutions was not disclosed. Single oral dosages of the solutions were administered to groups of 4 rats in doses of 100 mg/kg body weight. Surprisingly low rates of absorption were observed, as shown in their results presented in Table 1.
TABLE 1 ______________________________________ .sub.16 (.mu.g .multidot. hr/ml) C.sub.p (max), .mu.g/ml T.sub.max (hrs) AUC.sub.0 ______________________________________ probucol in medium 0.54 .+-. 0.1 7 .+-. 2 4.57 .+-. 1.0 chain triglyceride probucol in peanut 1.73 .+-. 0.2 5 .+-. 2 11.74 .+-. 1.6 oil ______________________________________
The above discussion shows that a need still exists for an optimized probucol delivery formulation. The desired formulation should be readily absorbed by the patient and should reach a high plasma concentration for a given dose. It should also exhibit absorption characteristics that do not vary greatly from individual to individual.